Plasmacytoid dendritic cells (PDCs) are a subtype of dendritic cells (DCs) defined largely by their unique capacity to secrete type-I interferons in response to antigen. Although it has been proposed that the specialized functional attributes of PDCs are dictated by their development, little is known regarding the cellular or molecular basis for PDC ontogeny. We have characterized a novel mouse mutant that exhibits a marked reduction in the frequency and absolute number of splenic PDCs with normal frequencies of B and T cells, non-lymphoid blood cells, and other DC subsets. These mice also lack a B-lineage derived bone marrow progenitor population that we have shown to differentiate into DCs in culture. Taken together, these findings suggest that PDCs develop primarily and perhaps entirely from this early B-lineage derived progenitor population. Therefore, we propose several experiments to further characterize these putative PDC precursors and to test that B cells and PDCs share a common developmental pathway. Specifically, we propose to: 1) Determine if defined lymphoid and myeloid progenitor populations generate PDCs in vivo; 2) Determine whether blockade of early B cell development results in a selective arrest in PDC development; and 3) Determine the timing with which PDC precursors acquire responsiveness to PDC-specific stimuli through the characterization of two putative PDC precursor populations in adult mouse bone marrow.